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The cortisol awakening response: regulation and functional significance. 皮质醇觉醒反应:调节和功能意义。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-23 DOI: 10.1210/endrev/bnae024
Tobias Stalder, Henrik Oster, James L Abelson, Katharina Huthsteiner, Tim Klucken, Angela Clow

In healthy individuals, the majority of cortisol secretion occurs within several hours surrounding morning awakening. A highly studied component of this secretory period is the cortisol awakening response (CAR), the rapid increase in cortisol levels across the first 30-45 min after morning awakening. This strong cortisol burst at the start of the active phase has been proposed to be functional in preparing the organism for the challenges of the upcoming day. Here, we review evidence on key regulatory and functional processes of the CAR and develop an integrative model of its functional role. Specifically, we propose that, in healthy individuals, the CAR is closely regulated by an intricate dual-control system, which draws upon key circadian, environmental and neurocognitive processes to best predict the daily need for cortisol-related action. Fine-tuned CAR expression, in turn, is then assumed to induce potent glucocorticoid action via rapid non-genomic and slower genomic pathways (e.g., affecting circadian clock gene expression) to support and modulate daily activity through relevant metabolic, immunological and neurocognitive systems. We propose that this concerted action is adaptive in mediating two main functions: a primary process to mobilize resources to meet activity-related demands and a secondary process to help the organism counterregulate adverse prior-day emotional experiences.

对于健康人来说,大部分皮质醇分泌发生在早晨醒来后的几个小时内。皮质醇唤醒反应(CAR)是这一分泌期中研究较多的一个组成部分,即皮质醇水平在早晨醒来后的前 30-45 分钟内迅速增加。活跃期开始时皮质醇的这种强烈迸发被认为是机体为迎接即将到来的一天的挑战做好准备的功能。在此,我们回顾了有关 CAR 关键调节和功能过程的证据,并对其功能作用建立了一个综合模型。具体来说,我们提出,在健康人体内,CAR 受到一个复杂的双重控制系统的密切调控,该系统利用关键的昼夜节律、环境和神经认知过程来最好地预测每日对皮质醇相关作用的需求。微调的 CAR 表达反过来又会通过快速的非基因组和较慢的基因组途径(如影响昼夜节律钟基因表达)诱导有效的糖皮质激素作用,从而通过相关的代谢、免疫和神经认知系统支持和调节日常活动。我们认为,这种协同作用在调解两个主要功能方面具有适应性:一个主要过程是调动资源以满足与活动有关的需求,另一个次要过程是帮助机体反调节前一天的不良情绪体验。
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引用次数: 0
Structure and Function of Somatostatin and its Receptors in Endocrinology. 内分泌学中的促生长素及其受体的结构和功能。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-08 DOI: 10.1210/endrev/bnae022
Bo Zhang, Li Xue, Zhe Bao Wu

Somatostatin analogs, such as octreotide (OCT), lanreotide, and pasireotide, which function as somatostatin receptor ligands (SRLs), are the main drugs used for the treatment of acromegaly. These ligands are also used as important molecules for radiation therapy and imaging of neuroendocrine tumors (NETs). Somatostatin receptors (SSTRs) are canonical G protein-coupled proteins (GPCRs) that play a role in metabolism, growth, and pathological conditions such as hormone disorders, neurological diseases, and cancers. Cryogenic electron microscopy (cryo-EM) combined with the protein structure prediction platform AlphaFold has been used to determine the three-dimensional structures of many proteins. Recently, several groups published a series of papers illustrating the three-dimensional structure of SSTR2, including that of the inactive/activated SSTR2-G protein complex bound to different ligands. The results revealed the residues that contribute to the ligand binding pocket and demonstrated that Trp8-Lys9 (the W-K motif) in somatostatin analogs is the key motif in stabilizing the bottom part of the binding pocket. In this review, we discuss the recent findings related to the structural analysis of SSTRs and SRLs, the relationships between the structural data and clinical findings, and the future development of novel structure-based therapies.

奥曲肽 (OCT)、兰雷奥肽和帕司雷奥肽等体生长抑素类似物作为体生长抑素受体配体 (SRL) 起作用,是治疗肢端肥大症的主要药物。这些配体也是神经内分泌肿瘤(NET)放射治疗和成像的重要分子。体生长抑素受体(SSTRs)是典型的 G 蛋白偶联蛋白(GPCRs),在新陈代谢、生长以及激素紊乱、神经系统疾病和癌症等病理情况中发挥作用。低温电子显微镜(cryo-EM)结合蛋白质结构预测平台 AlphaFold 已被用于确定许多蛋白质的三维结构。最近,几个研究小组发表了一系列论文,展示了 SSTR2 的三维结构,包括与不同配体结合的非活性/活性 SSTR2-G 蛋白复合物的三维结构。研究结果揭示了有助于配体结合袋的残基,并证明体生长抑素类似物中的 Trp8-Lys9(W-K 基团)是稳定结合袋底部的关键基团。在这篇综述中,我们将讨论有关 SSTR 和 SRL 结构分析的最新发现、结构数据与临床发现之间的关系以及基于结构的新型疗法的未来发展。
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引用次数: 0
Adiponectin and Adiponectin Receptors in Atherosclerosis. 动脉粥样硬化中的脂肪连接素和脂肪连接素受体
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-08-06 DOI: 10.1210/endrev/bnae021
Ioanna Gianopoulos, Christos S Mantzoros, Stella S Daskalopoulou

Adiponectin is an abundantly secreted hormone that communicates information between the adipose tissue, and the immune and cardiovascular systems. In metabolically healthy individuals, adiponectin is usually found at high levels and helps improve insulin responsiveness of peripheral tissues, glucose tolerance, and fatty acid oxidation. Beyond its metabolic functions in insulin-sensitive tissues, adiponectin plays a prominent role in attenuating the development of atherosclerotic plaques, partially through regulating macrophage-mediated responses. In this context, adiponectin binds to its receptors, adiponectin receptor 1 (AdipoR1) and AdipoR2 on the cell surface of macrophages to activate a downstream signaling cascade and induce specific atheroprotective functions. Notably, macrophages modulate the stability of the plaque through their ability to switch between pro-inflammatory responders, and anti-inflammatory pro-resolving mediators. Traditionally, the extremes of the macrophage polarization spectrum span from M1 pro-inflammatory and M2 anti-inflammatory phenotypes. Previous evidence has demonstrated that the adiponectin-AdipoR pathway influences M1-M2 macrophage polarization; adiponectin promotes a shift towards an M2-like state, whereas AdipoR1- and AdipoR2-specific contributions are more nuanced. To explore these concepts in depth, we discuss in this review the impact of adiponectin and AdipoR1/R2 on 1) metabolic and immune responses, and 2) M1-M2 macrophage polarization, including their ability to attenuate atherosclerotic plaque inflammation, and their potential as therapeutic targets for clinical applications.

脂肪连通素是一种大量分泌的激素,可在脂肪组织、免疫系统和心血管系统之间传递信息。在新陈代谢健康的人体内,脂肪连通素的含量通常很高,有助于改善外周组织对胰岛素的反应、葡萄糖耐量和脂肪酸氧化。除了在胰岛素敏感组织中发挥新陈代谢功能外,脂肪连通素还部分通过调节巨噬细胞介导的反应,在减少动脉粥样硬化斑块的形成方面发挥着重要作用。在这种情况下,脂肪连通素与其受体--巨噬细胞细胞表面的脂肪连通素受体 1(AdipoR1)和 AdipoR2 结合,激活下游信号级联,诱导特定的动脉粥样硬化保护功能。值得注意的是,巨噬细胞通过在促炎症反应介质和抗炎症促溶解介质之间切换的能力来调节斑块的稳定性。传统上,巨噬细胞极化谱的两极包括 M1 促炎表型和 M2 抗炎表型。以往的证据表明,脂肪连通素-AdipoR通路影响着M1-M2巨噬细胞的极化;脂肪连通素促进向类似M2的状态转变,而AdipoR1-和AdipoR2-特异性的贡献则更为细微。为了深入探讨这些概念,我们在这篇综述中讨论了脂肪连接素和 AdipoR1/R2 对 1)代谢和免疫反应以及 2)M1-M2 巨噬细胞极化的影响,包括它们减轻动脉粥样硬化斑块炎症的能力,以及它们作为临床应用治疗靶点的潜力。
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引用次数: 0
Molecular developments in parasellar tumors and potential therapeutic implications. 寄生虫肿瘤的分子发展及潜在治疗意义。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-26 DOI: 10.1210/endrev/bnae020
Paraskevi Xekouki, Vasiliki Venetsanaki, Georgios Kyriakopoulos, Krystallenia Alexandraki, Anna Angelousi, Gregory Kaltsas

The parasellar region is the anatomical area around the sella turcica that represents a crucial crossroad for important adjacent structures. Several distinct tumors can primarily originate from this area, the most common being meningiomas, gliomas, embryonal cell tumors, germ cell tumors and craniopharyngiomas. In addition, a number of systemic and inflammatory disorders can also affect the parasellar region most commonly involving the pituitary. These lesions have different pathology characteristics and malignant potential according to the new WHO CNS5 2021 classification. Signs and symptoms may be non-specific and are mostly related to a mass effect on the surrounding anatomical structures and/or impairment of endocrine function whereas the vast majority lack a secretory component. The mutational signature analysis based on advances in molecular techniques, has recently enabled the identification of specific gene mutations or signalling pathway aberrations. These developments may serve as a powerful mean to delineate the pathophysiology of these lesions and serve as a diagnostic, prognostic and therapeutic tool, particularly for high-risk populations. Treatment options include surgery alone or in combination with radiotherapy, chemotherapy and disease-specific medical therapy in order to prevent recurrence or further tumor growth along with replacement of coexistent pituitary hormonal deficiencies. In this comprehensive review, we present current state-of-the-art developments in the histopathology and molecular biology of these lesions that may be utilized by a dedicated multidisciplinary team of relevant specialties for the diagnosis, monitoring and treatment of the parasellar lesions that often represent a diagnostic and therapeutic challenge.

蝶鞍旁区域是蝶鞍周围的解剖区域,是重要邻近结构的关键交叉点。有几种不同的肿瘤可能主要起源于这一区域,其中最常见的是脑膜瘤、胶质瘤、胚胎细胞瘤、生殖细胞瘤和颅咽管瘤。此外,一些全身性和炎症性疾病也会影响蝶鞍旁区域,最常见的是脑垂体。根据世界卫生组织新的 CNS5 2021 分类法,这些病变具有不同的病理特征和恶性潜能。体征和症状可能是非特异性的,大多与对周围解剖结构的肿块效应和/或内分泌功能损害有关,而绝大多数缺乏分泌成分。基于分子技术进步的突变特征分析最近已能识别特定的基因突变或信号通路畸变。这些研究成果可作为一种强有力的手段,用于描述这些病变的病理生理学,并作为诊断、预后和治疗工具,尤其是针对高危人群。治疗方案包括单独手术或结合放疗、化疗和针对特定疾病的药物治疗,以防止肿瘤复发或进一步生长,同时替代并存的垂体激素缺乏症。在这篇综述中,我们介绍了这些病变的组织病理学和分子生物学的最新进展,相关专科的多学科团队可利用这些进展来诊断、监测和治疗寄生虫病变,这些病变往往是诊断和治疗方面的难题。
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引用次数: 0
Mini-Puberty, Physiological and Disordered: Consequences, and Potential for Therapeutic Replacement. 小青春期,生理性和失调性:后果和治疗替代的潜力。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-12 DOI: 10.1210/endrev/bnae003
Julia Rohayem, Emma C Alexander, Sabine Heger, Anna Nordenström, Sasha R Howard

There are 3 physiological waves of central hypothalamic-pituitary-gonadal (HPG) axis activity over the lifetime. The first occurs during fetal life, the second-termed "mini-puberty"-in the first months after birth, and the third at puberty. After adolescence, the axis remains active all through adulthood. Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder characterized by a deficiency in hypothalamic gonadotropin-releasing hormone (GnRH) secretion or action. In cases of severe CHH, all 3 waves of GnRH pulsatility are absent. The absence of fetal HPG axis activation manifests in around 50% of male newborns with micropenis and/or undescended testes (cryptorchidism). In these boys, the lack of the mini-puberty phase accentuates testicular immaturity. This is characterized by a low number of Sertoli cells, which are important for future reproductive capacity. Thus, absent mini-puberty will have detrimental effects on later fertility in these males. The diagnosis of CHH is often missed in infants, and even if recognized, there is no consensus on optimal therapeutic management. Here we review physiological mini-puberty and consequences of central HPG axis disorders; provide a diagnostic approach to allow for early identification of these conditions; and review current treatment options for replacement of mini-puberty in male infants with CHH. There is evidence from small case series that replacement with gonadotropins to mimic "mini-puberty" in males could have beneficial outcomes not only regarding testis descent, but also normalization of testis and penile sizes. Moreover, such therapeutic replacement regimens in disordered mini-puberty could address both reproductive and nonreproductive implications.

在人的一生中,下丘脑-垂体-性腺轴(HPG)的中枢活动有三个生理波段。第一波发生在胎儿时期,第二波被称为 "小青春期",发生在出生后的头几个月,第三波发生在青春期。青春期过后,该轴在整个成年期都会保持活跃。先天性性腺功能减退症(CHH)是一种罕见的遗传性疾病,其特点是下丘脑促性腺激素释放激素(GnRH)分泌或作用不足。在严重的 CHH 病例中,GnRH 的三波搏动都不存在。胎儿 HPG 轴激活缺失表现为约 50% 的男性新生儿有小阴茎和/或睾丸下降不全(隐睾症)。在这些男孩中,小青春期的缺失凸显了睾丸的不成熟。其特点是塞尔托利细胞数量少,而塞尔托利细胞对未来的生殖能力非常重要。因此,小青春期的缺失将对这些男性日后的生育能力产生不利影响。婴儿 CHH 的诊断常常被漏诊,即使确诊,最佳治疗方法也没有达成共识。在此,我们回顾了生理性小头畸形和 HPG 轴中枢紊乱的后果;提供了一种诊断方法,以便及早发现这些病症;并回顾了目前替代 CHH 男婴小头畸形的治疗方案。有小型病例系列的证据表明,用促性腺激素替代来模拟男性的 "小青春期 "不仅在睾丸下降方面有益,而且还能使睾丸和阴茎大小正常化。此外,对发育紊乱的 "小青春期 "采取这种治疗替代方案,可以解决生殖和非生殖方面的问题。
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引用次数: 0
Genetic and Epigenetic Landscape for Drug Development in Polycystic Ovary Syndrome. 多囊卵巢综合症药物开发的基因和表观遗传学前景。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-12 DOI: 10.1210/endrev/bnae002
Yi Chen, Guiquan Wang, Jingqiao Chen, Congying Wang, Xi Dong, Hsun-Ming Chang, Shuai Yuan, Yue Zhao, Liangshan Mu

The treatment of polycystic ovary syndrome (PCOS) faces challenges as all known treatments are merely symptomatic. The US Food and Drug Administration has not approved any drug specifically for treating PCOS. As the significance of genetics and epigenetics rises in drug development, their pivotal insights have greatly enhanced the efficacy and success of drug target discovery and validation, offering promise for guiding the advancement of PCOS treatments. In this context, we outline the genetic and epigenetic advancement in PCOS, which provide novel insights into the pathogenesis of this complex disease. We also delve into the prospective method for harnessing genetic and epigenetic strategies to identify potential drug targets and ensure target safety. Additionally, we shed light on the preliminary evidence and distinctive challenges associated with gene and epigenetic therapies in the context of PCOS.

多囊卵巢综合症(PCOS)的治疗面临挑战,因为所有已知的治疗方法都只是对症治疗。美国食品和药物管理局(FDA)尚未批准任何专门用于治疗多囊卵巢综合症的药物。随着遗传学和表观遗传学在药物开发中的重要性不断提高,它们的重要见解大大提高了药物靶点发现和验证的效率和成功率,为指导多囊卵巢综合症治疗的进步带来了希望。在此背景下,我们概述了多囊卵巢综合症的遗传学和表观遗传学进展,这些进展为这一复杂疾病的发病机制提供了新的见解。我们还深入探讨了利用基因和表观遗传学策略识别潜在药物靶点并确保靶点安全性的前瞻性方法。此外,我们还阐明了与多囊卵巢综合症相关的基因和表观遗传疗法的初步证据和独特挑战。
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引用次数: 0
The Search for the Causes of Common Hyperandrogenism, 1965 to Circa 2015. 寻找常见雄激素过多症的原因,1965 年至 2015 年左右。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-12 DOI: 10.1210/endrev/bnae007
Robert L Rosenfield

From 1965 to 2015, immense strides were made into understanding the mechanisms underlying the common androgen excess disorders, premature adrenarche and polycystic ovary syndrome (PCOS). The author reviews the critical discoveries of this era from his perspective investigating these disorders, commencing with his early discoveries of the unique pattern of plasma androgens in premature adrenarche and the elevation of an index of the plasma free testosterone concentration in most hirsute women. The molecular genetic basis, though not the developmental biologic basis, for adrenarche is now known and 11-oxytestosterones shown to be major bioactive adrenal androgens. The evolution of the lines of research into the pathogenesis of PCOS is historically traced: research milestones are cited in the areas of neuroendocrinology, insulin resistance, hyperinsulinism, type 2 diabetes mellitus, folliculogenesis, androgen secretion, obesity, phenotyping, prenatal androgenization, epigenetics, and complex genetics. Large-scale genome-wide association studies led to the 2014 discovery of an unsuspected steroidogenic regulator DENND1A (differentially expressed in normal and neoplastic development). The splice variant DENND1A.V2 is constitutively overexpressed in PCOS theca cells in long-term culture and accounts for their PCOS-like phenotype. The genetics are complex, however: DENND1A intronic variant copy number is related to phenotype severity, and recent data indicate that rare variants in a DENND1A regulatory network and other genes are related to PCOS. Obesity exacerbates PCOS manifestations via insulin resistance and proinflammatory cytokine excess; excess adipose tissue also forms testosterone. Polycystic ovaries in 40 percent of apparently normal women lie on the PCOS functional spectrum. Much remains to be learned.

从 1965 年到 2015 年,人们在了解常见的雄激素过多疾病--过早性腺发育和多囊卵巢综合征(PCOS)的发病机制方面取得了巨大进步。作者从他研究这些疾病的角度回顾了这一时期的重要发现,首先是他早期发现早衰性肾上腺皮质激素的独特模式,以及大多数多毛女性血浆游离睾酮浓度指数的升高。现在,人们已经知道了肾上腺早熟的分子遗传学基础(尽管不是发育生物学基础),并证明 11-氧睾酮是具有生物活性的主要肾上腺雄激素。多囊卵巢综合症发病机制研究路线的演变可追溯到历史:在神经内分泌学、胰岛素抵抗、高胰岛素血症、2 型糖尿病、卵泡生成、雄激素分泌、肥胖、表型、产前雄激素化、表观遗传学和复杂遗传学等领域的研究具有里程碑意义。大规模的全基因组关联研究促使人们在2014年发现了一种未被察觉的类固醇生成调节因子DENND1A(在正常和肿瘤性发育过程中差异表达)。剪接变体DENND1A.V2在长期培养的多囊卵巢综合征(PCOS)绒毛膜细胞中构成性过表达,并导致其多囊卵巢综合征样表型。然而,遗传学是复杂的:DENND1A 内含子变异拷贝数与表型严重程度有关,最近的数据表明,DENND1A 调控网络和其他基因中的罕见变异与多囊卵巢综合症有关。肥胖会通过胰岛素抵抗和促炎症细胞因子过多加剧多囊卵巢综合症的表现;过多的脂肪组织还会形成睾酮。四分之一表面上正常的女性患有多囊卵巢综合症,这属于多囊卵巢综合症的功能范围。还有许多问题有待了解。
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引用次数: 0
Preclinical Rodent Models for Human Bone Disease, Including a Focus on Cortical Bone. 人类骨病的临床前啮齿动物模型,包括皮质骨。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-12 DOI: 10.1210/endrev/bnae004
Natalie Y Y Koh, Justyna J Miszkiewicz, Mary Louise Fac, Natalie K Y Wee, Natalie A Sims

Preclinical models (typically ovariectomized rats and genetically altered mice) have underpinned much of what we know about skeletal biology. They have been pivotal for developing therapies for osteoporosis and monogenic skeletal conditions, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and craniodysplasias. Further therapeutic advances, particularly to improve cortical strength, require improved understanding and more rigorous use and reporting. We describe here how trabecular and cortical bone structure develop, are maintained, and degenerate with aging in mice, rats, and humans, and how cortical bone structure is changed in some preclinical models of endocrine conditions (eg, postmenopausal osteoporosis, chronic kidney disease, hyperparathyroidism, diabetes). We provide examples of preclinical models used to identify and test current therapies for osteoporosis, and discuss common concerns raised when comparing rodent preclinical models to the human skeleton. We focus especially on cortical bone, because it differs between small and larger mammals in its organizational structure. We discuss mechanisms common to mouse and human controlling cortical bone strength and structure, including recent examples revealing genetic contributors to cortical porosity and osteocyte network configurations during growth, maturity, and aging. We conclude with guidelines for clear reporting on mouse models with a goal for better consistency in the use and interpretation of these models.

临床前模型(通常是切除卵巢的大鼠和基因改变的小鼠)为我们了解骨骼生物学奠定了基础。它们在开发骨质疏松症和单基因骨骼疾病(包括成骨不全症、软骨发育不全症、软骨发育不全症和颅骨发育不全症)的疗法方面发挥了关键作用。要取得进一步的治疗进展,尤其是改善皮质强度,就必须加深了解并更严格地使用和报告。我们在此描述小鼠、大鼠和人类骨小梁和骨皮质结构是如何发育、维持和随着年龄增长而退化的,以及在内分泌疾病(如绝经后骨质疏松症、慢性肾病、甲状旁腺功能亢进、糖尿病)的临床前模型中骨皮质结构是如何变化的。我们将举例说明用于确定和测试当前骨质疏松症疗法的临床前模型,并讨论将啮齿动物临床前模型与人体骨骼进行比较时常见的问题。我们尤其关注皮质骨,因为小型哺乳动物和大型哺乳动物的皮质骨在组织结构上有所不同。我们讨论了小鼠和人类控制皮质骨强度和结构的共同机制,包括最近揭示了生长、成熟和老化过程中皮质孔隙率和骨细胞网络配置的遗传因素。最后,我们提出了明确报告小鼠模型的指导原则,目的是更好地统一这些模型的使用和解释。
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引用次数: 0
The Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives. 嗜铬细胞瘤和副神经节瘤的免疫格局:当前进展与前景。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-12 DOI: 10.1210/endrev/bnae005
Ondrej Uher, Katerina Hadrava Vanova, David Taïeb, Bruna Calsina, Mercedes Robledo, Roderick Clifton-Bligh, Karel Pacak

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells from adrenal medullary chromaffin tissues and extra-adrenal paraganglia, respectively. Although the current treatment for PPGLs is surgery, optimal treatment options for advanced and metastatic cases have been limited. Hence, understanding the role of the immune system in PPGL tumorigenesis can provide essential knowledge for the development of better therapeutic and tumor management strategies, especially for those with advanced and metastatic PPGLs. The first part of this review outlines the fundamental principles of the immune system and tumor microenvironment, and their role in cancer immunoediting, particularly emphasizing PPGLs. We focus on how the unique pathophysiology of PPGLs, such as their high molecular, biochemical, and imaging heterogeneity and production of several oncometabolites, creates a tumor-specific microenvironment and immunologically "cold" tumors. Thereafter, we discuss recently published studies related to the reclustering of PPGLs based on their immune signature. The second part of this review discusses future perspectives in PPGL management, including immunodiagnostic and promising immunotherapeutic approaches for converting "cold" tumors into immunologically active or "hot" tumors known for their better immunotherapy response and patient outcomes. Special emphasis is placed on potent immune-related imaging strategies and immune signatures that could be used for the reclassification, prognostication, and management of these tumors to improve patient care and prognosis. Furthermore, we introduce currently available immunotherapies and their possible combinations with other available therapies as an emerging treatment for PPGLs that targets hostile tumor environments.

嗜铬细胞瘤和副神经节瘤(PPGLs)是一种罕见的神经内分泌肿瘤,分别来自肾上腺髓质绒毛组织或肾上腺外副神经节的神经嵴细胞。虽然目前治疗 PPGLs 的方法是手术,但晚期和转移性病例的最佳治疗方案却很有限。因此,了解免疫系统在 PPGL 肿瘤发生过程中的作用可为制定更好的治疗和肿瘤管理策略提供必要的知识,尤其是对晚期和转移性 PPGL 患者而言。本综述的第一部分概述了免疫系统和肿瘤微环境的基本原理,以及它们在癌症免疫调节中的作用,特别强调了 PPGLs。我们将重点讨论 PPGLs 独特的病理生理学,如其高度的分子、生化和成像异质性以及多种肿瘤代谢产物的产生,是如何形成肿瘤特异性微环境和免疫学上 "冷 "的肿瘤的。随后,我们将讨论近期发表的基于免疫特征对 PPGLs 进行再聚类的相关研究。综述的第二部分讨论了 PPGL 管理的未来前景,包括将 "冷 "肿瘤转化为免疫活跃或 "热 "肿瘤的免疫诊断和有前景的免疫治疗方法,这些肿瘤因其更好的免疫治疗反应和患者预后而闻名。我们特别强调了有效的免疫相关成像策略和免疫特征,可用于这些肿瘤的重新分类、预后和管理,以改善患者护理和预后。此外,我们还介绍了目前可用的免疫疗法及其与其他可用疗法的可能组合,作为针对恶劣肿瘤环境的新兴 PPGLs 治疗方法。
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引用次数: 0
The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity. 糖皮质激素受体:同工型、功能和对糖皮质激素敏感性的贡献。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2024-07-12 DOI: 10.1210/endrev/bnae008
Jack Lockett, Warrick J Inder, Vicki L Clifton

Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-inflammatory benefits of glucocorticoids were mediated by transrepression of pro-inflammatory transcription factors, while the adverse metabolic effects resulted from direct transactivation. This canonical understanding of the GR function has been brought into question over the past 2 decades with advances in the resolution of scientific techniques, and the discovery of multiple isoforms of the receptor present in most tissues. Here we review the structure and function of the GR, the nature of the receptor isoforms, and the contribution of the receptor to glucocorticoid sensitivity, or resistance in health and disease.

糖皮质激素对所有组织都有多方面的影响,可调节细胞和新陈代谢的平衡。合成糖皮质激素可用于治疗多种疾病,具有抗炎作用,但其副作用与剂量和持续时间有关。不同组织、不同疾病状态和不同个体之间,糖皮质激素的益处和副作用都存在显著差异。糖皮质激素受体是这些激素的作用部位,人们已对其功能进行了大量研究。传统上,人们认为糖皮质激素的抗炎作用是通过转抑促炎转录因子介导的,而对代谢的不利影响则是直接转激活的结果。过去二十年来,随着科学技术分辨率的提高和大多数组织中糖皮质激素受体多种异构体的发现,这种对糖皮质激素受体功能的传统认识受到了质疑。在此,我们回顾了糖皮质激素受体的结构和功能、受体异构体的性质以及受体对糖皮质激素的敏感性或在健康和疾病中的抵抗力的贡献。
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引用次数: 0
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Endocrine reviews
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